With the advent of new technological, scientific advances and findings in the fields of oncology, microbiology and epidemiology, there has been a growing interest among scientists and physicians to develop new medicines having carcinostatic effects and methods to control the spread of diseases and inhibit and greatly reduce the infectivity of certain harmful microorganisms. Pathogens such as viruses, bacteria, and fungi have been known to cause a plethora of human, animal and plant diseases and illnesses along with the concomitant contamination of food, and biological and environmental samples. Of particular interest are those pathogens, which are associated with incurable and often fatal diseases such as acquired immune deficiency syndrome or commonly referred to as AIDS, the various forms of hepatitis, cytomegalovirus, and the like. Bacterial infections such as those linked to the Bacillus genus, which form stable spores that can withstand and sustain harsh conditions, and extreme temperatures are other such microorganisms; for example, B. antharcis leads to a fatal disease in humans, domestic, agricultural and wild animals. Human contamination results from contact with infected animals, and recently another route of contamination is via terrorist activities and/or biological warfare. Other examples of bacteria that can have deleterious effects, which develop resistance, include the genus Staphylococcus that often can cause fatal infections, Pneumococci that can cause meningitis and pneumonia, and Enterococci that can cause infections of surgical wound, urinary tract and blood.
The current treatments for cell proliferation diseases such as cancer and psoriasis employ cytotoxic heavy metals, which inhibit cell division and DNA replication. Examples of such metals are gold, titanium, tin, copper, vanadium, iridium, rhodium, and the like (Haiduc, I. & Silvestru, C., In Vivo, 4, 285 (1989); Caruso, F., et al., J. Med. Chem, 43, 3665 (2000); and Caruso, F., et al., Expert. Opin. Ther. Patents, 11, 969 (2001)). The most prominent and promising family of cytotoxic agents is those referred to as “oxaliplatin”, also known as L-OHP. These agents utilize platinum as the heavy metal and are considered a third generation platinum complexes. These include those disclosed following the procedure described in Kidani et al., U.S. Pat. No. 4,169,846; Tanaka, U.S. Pat. Nos. 5,290,961, 5,298,642, 5,338,874, 5,420,319, 5,959,133 and European patent application No. 715,854; SmithKline Beecham, U.S. Pat. No. 5,633,016; Debiopharm, International patent applications WO 94/12193 and WO 01/15691, European patent application No. 1121117 and U.S. Pat. No. 5,716,988; Pharmacia & Upjohn Co., U.S. Pat. No. 6,287,593; Sanofi-Synthelabo, U.S. Pat. Nos. 6,063,780 and 6,306,902; BioNumerik, U.S. Pat. No. 6,066,666; and Bristol-Myers Squibb, International patent application WO 01/66102, incorporated herein in their entirety by reference. This class of drugs has entered the market through its in vitro and in vivo cytotoxic activity, and its good clinical tolerance, e.g., the absence of renal or auditory toxicity being combined with a low hematotoxicity.
Other methods have relied upon the use of ultra-violet irradiated silver fluoride solutions containing silver as a source of germicide activities, such as U.S. Pat. No. 3,422,183, incorporated herein in its entirety by reference. However, such techniques require expensive equipment and large amounts of electricity.
Hydrogen peroxide is a strong oxidizing agent, and it has been used for the past 40 years as a disinfectant. Its main advantage is that it does not produce toxic residue or by-products. It has been used ubiquitously as an indirect food additive, as a disinfectant in hospitals, as a decontamination and purification agent of industrial wastewater, and as a cleaning agent for exhaust air. Nonetheless, it decomposes readily to form water and oxygen, and has high sensitivity to sunlight and UV rays. Therefore, it is not suited for long-term use since recontamination cannot be circumvented.
In 1880, the Swiss botanist Carl van Nageli observed that highly diluted silver solutions have an algicidal effect. To describe this effect he coined the term “Oligodynamic”. Colloidal silver, which is a pure, all-natural substance consisting of sub-microscopic clusters of silver ions held in suspension in de-ionized water by tiny positive charges on the silver ions, is a powerful prophylactic antibiotic which was used for years with no known side effects. It acts as an inhibitor disabling particular enzymes which bacteria, fungi, and viruses used in their mode of metabolism.
Based on this oligodynamic property, U.S. Pat. No. 4,915,955, incorporated in its entirety herein by reference, combines the germicidal effects of hydrogen peroxide with silver, an inorganic acid, and an organic stabilizer at concentrations of 10-35 mg/l to combat many forms of bacteria and viruses. The process is based on silver ions, with the aid of hydrogen peroxide, damaging the protective biofilms of these microorganisms. Hence, this method depends solely on killing germs intercellularly.
U.S. Pat. No. 6,242,009, incorporated herein in its entirety by reference, describes the formation of metal complexes suitable as disinfectants and sanitizers to combat pathogenic microorganisms. It relies on using metal ions and amino acids to form complexes, which serve as carriers for metals, in order to diffuse into the intra-cellular medium of such microorganisms where it exhibits its biocidal activities. The composition can be prepared by mixing a metal salt compound in an aqueous solution, and an inorganic acid at room temperature to adjust the pH of the solution; adding at least on an equimolar basis, depending on the valency of the metals, at least one amino acid to form an insoluble metal complex while homogenizing the mixture; and depending on its use, the resultant solution can then be proportioned with various ratios to make suitable disinfectants by adding appropriate amount of distilled-deionized water and/or hydrogen peroxide.
U.S. Pat. No. 6,630,172, incorporated herein in its entirety by reference, delves on the use of organo-metallic complexes that can be employed as microbicides to combat pathogenic microorganisms. It is based on using metal ions and potassium sodium tartrate to form organo-metallic chelates where these chelates can exhibit its microbicidal activities. The composition can be prepared by mixing a metal salt compound in an aqueous solution, and an inorganic acid at room temperature to adjust the pH of the solution; adding potassium sodium tartrate in at least one fourth of the molar amount with respect to the valency of the designated metal while homogenizing the mixture; depending on its use, the resultant solution can then be proportioned with various ratios to make suitable disinfectants by adding appropriate amount of distilled-deionized water and/or hydrogen peroxide. Optionally, amino acids can be added to the mixture to enhance metal chelation.
Although various robust methods and techniques have been employed to combat cancer and pathogens, cancer and antimicrobial therapy suffers from various deficiencies. Cancer therapy nowadays involves a multi-modality approach of one or a combination of radiation, chemotherapy, hormone therapy, immunotherapy, and antiangiogenic drugs (non-cytotoxic class of anti-tumor agents that inhibit the development of new blood vessels from older ones). Surgery, on the other hand, involves the bulk removal of diseased tissue. While surgery is sometimes effective in removing neoplasms, or tumors (unregulated and disorganized proliferation of cell) located at certain sites, for example, in the breast, colon, and skin, it cannot be used in the treatment of tumors located in other areas, such as the backbone, nor in the treatment of disseminated neoplastic conditions such as leukemia. If portions of the primary tumor cannot be removed or if it is believed to have metastasized, systemic drug therapy is given to kill residual cancerous cells through targeting of actively dividing cells.
There are difficulties associated with cancerous compounds in that effective treatment is hampered due to lack of specificity and difficulty in delivering these agents to the site of the carcinogenic tumors. This is especially true with using chemotherapeutic and cytotoxic agents with neoplasms where within the intra-or-inner-region of neoplasm the network of blood capillaries is too small for such agents to be delivered (Jain, R., Cancer Metastasis Rev., 9, 253 (1990); Forbes, N. S., et al., Cancer Research, 63, 5188 (2003); Znati, C. A., et al., Clinical Cancer Research, 9, 5508 (2003); Jain, R. K., Nature Medicine, 9, 685 (2003); Jain, R. K., & M. F. Booth, J. Clinical Investigation, 112, 1134 (2003); and Jain, R. K. Vascular and Interstitial Biology of Tumors (Chapter 9). In M. Abeleff, J. Armtage, M. Kastan, G. McKenna, J. Niederhuber, and D. Meloni (ed.), Clinical Oncology, 3rd Edition, in press. Elsevier, Philadelphia, Pa.). These regions are commonly exist in most major classes of solid tumors such as those associated with breast, head and neck, pancreatic, stomach, ovarian, cervical, lung, and prostate tumors. The present organic moieties, therefore, have smaller molecular weights from which smaller size chemotherapeutic molecules can be developed to combat neoplasms.
Additionally, there is the problem of the patient developing a resistance with the continual and the prolong use of such agents. Also, the many adverse side effects associated with the current systemic therapeutic methods used for the treatment of cancer make the current invention an excellent candidate for alternative therapy. These induced side effects significantly impact the quality of life of the patient and sometimes dramatically influence the patient compliance with the treatment regiment. These complications include cytopenia, cachexia, infections, mucositis, especially in patients receiving high doses of chemotherapy with bone marrow rescue or radiation therapy, alopecia, pruritis, urticaria, and angioedema, and many others related to pulmonary, cardiac, reproductive and endocrine. These complications are the major dose-limiting toxicity and can lead to hospitalization of the patient and analgesics for the alleviation of pain. In addition, the toxicity of these agents renders them to be particularly dangerous and risk of contamination during manufacturing and reconstitution to workers, pharmacists, medical personnel, and nurses.
The overwhelming use of antibiotic and antiviral drugs has resulted in a worldwide epidemic, especially when strains of various pathogens appear resistant to antibiotics and antiviral medications. This problem is becoming a major crisis since these new strains of bacteria cause deadly infections, which are extremely difficult to treat, resulting in necrosis and death in many instances. Aside from microorganisms' mutation, they are also associated with numerous negative side effects, including killing the flora, fatigue, gastrointestinal upsets, candidiasis, severe skin rashes, kidney and renal infections, diarrhoea, colitis, hearing loss and many more.
With respect to biocides that rely on the use of chemical adjuvants such as aldehydes, phenols, alcohol, potassium permanganate, and chlorine and certain chlorine containing compounds have many disadvantages associated with them. This is mainly due to toxicity that leads to tissue necrosis upon administration and pulmonary injuries after inhalation of volatile gases and fumes. In addition, the corrosive nature of such compounds renders them unsuitable for disinfection of sensitive equipment, and people coming into contact with these substances can develop skin irritation and suffer from long time illnesses, which in some cases can be fatal; not to mention the unpleasant taste and odor associated with these chemicals. In addition, formation of mutagenic and carcinogenic agents, and genetically resistant strains are also some of their disadvantages. Notwithstanding, such compounds have afforded a way to battle these harmful microorganisms and their effectiveness has been unequivocally demonstrated.
Accordingly, there is an immediate need to develop and design new generation of chemotherapeutic, and antipathogenic agents that are able to overcome the above-described disadvantages, and lower the infectivity and mortality of those associated with pathogens. Thus, formulation of novel chemotherapeutic and antimicrobial compositions is necessarily ad hoc. Such compositions should overcome one or more of the above-described disadvantages, and concurrently being nontoxic, noncorrosive and nonirritant to the recipient. Also, it is an object of the present invention to provide compounds, which upon administration rapidly break down to release their chemotherapeutic agent, and realize their cytotoxic effect with minimum negative side effects.